DESCRIPTION: (Applicant's Abstract) Cocaine addiction is a complex and multi-dimensional problem that has defied conventional medical, psychological and legal interventions. Although behavioral modification procedures that promote abstinence are optimal strategies, they have not been successful. Mounting evidence indicates that pharmacological agents are required to treat cocaine addiction. The long-term goals of this research are to develop medications for the management of cocaine addiction. The specific goals are to investigate promising novel compounds with strategies that can be applied directly to human studies. Although progress has been made in the use of animal models to study cocaine's effects on the brain, most animal studies cannot be repeated in human subjects. Positron emission tomography (PET) offers a unique opportunity for studying the cerebral biochemistry and pharmacology of candidate therapeutics for cocaine abuse at the preclinical level, and for applying the same techniques in the clinical phase of the research. The applicants propose to use PET imaging techniques to investigate whether dopaminergic compounds display pharmacokinetic and pharmacodynamic properties that may be appropriate for treating cocaine dependency. Two classes of compounds will be investigated, dopamine transporter inhibitors developed with a chemist-collaborator, Dr. Peter Meltzer, and D1 dopamine receptor agonists. The applicants will investigate the feasibility of identifying dopamine transporter drugs that bind to the dopamine transporter at sufficiently high levels to prevent access to [11C]cocaine. Such compounds may effectively serve as both cocaine replacements and as cocaine antagonists. Subsequently, these compounds will be administered chronically, with a view of determining whether transporter blockade persists. It is hypothesized that the D1 dopamine receptor, an indirect target of cocaine, is subject to profound regulatory processes which may contribute to or detract from the therapeutic potential of candidate drugs. Based on this theory, studies will investigate the effects of candidate compounds or D1 receptor availability using [11C]SCH23390 to image the sites. This approach will provide lead compounds for further assessment as cocaine medications and strategies directly applicable to human studies.